ProjectSummary Clinicaldisordersarisingfrommaladaptiveemotionregulationpresentalargeburdenonsociety worldwide.Manyofthesedisordersshowcomorbidity,forexample,addictionwithanxietydisorders. Cuespredictingsomethingaversiveelicitavoidanceandfearbehaviorswhereascuespredicting rewardelicitapproachandreward-seekingbehaviors.Cuessignifyingsafetyhavethepowerto modulatefearandreward-seekingbehaviorsbyinformingtheorganismwhetherornottheenvironment issafe.Thus,safety,fearandrewardbehaviors,andthecircuitriesgoverningthesebehaviors,are intertwined.Themajorityofstudiesonrewardandfearprocessinghavebeenconductedinparallel, investigatingthecircuitriesseparatelyinprimarilymalesubjects.Ifwehopetounderstandandtreat comorbiddisordersresultingfrommaladaptiveemotionregulationincreasedeffortsininvestigatinghow thesecircuitriesintegratetheirfunctionstoinfluencebehaviorisneededinbothmaleandfemale subjects.Theproposedworkusesanovelbehavioralparadigmexplicitlydesignedtoassesssafety, fearandrewardcuelearningtogetherinordertoinvestigatethemultiplecircuitriesthatregulatethese learningprocessesinaratmodel.Ourresultsshowthat,comparedtomales,femaleratsdonotshow suppressionofconditionedfearinthepresenceofthesafetycue,indicatingafailuretoregulatefearin ?safe?conditions,andtheyaremorerewardresponsiveduringtherewardcue.Sincewomenaremore thantwiceaslikelyasmentodevelopemotiondysregulationdisorders,thisparadigmoffersagreat opportunitytoteaseapartthesexdifferencesinneuralcircuitrythataregeneratingthebehavioralsex differences.Together,theproposedaimsaredesignedtoidentifytheneuralcircuitryandmechanisms ofsafety,fearandrewardcuediscriminationandhowtheymaydifferbetweenmalesandfemales. Aims1and2focusontheinfralimbicprefrontalcortex,prelimbicprefrontalcortexandbasolateral amygdalainmaleandfemaleratstoidentifydifferencesinneuralactivityandthecriticalprojections amongthesebrainregionsduringsafety-fear-rewarddiscrimination.Aim3focusesontheprojection fromtheventraltegmentalareatothebasolateralamygdalainmaleandfemalerats.Weexpectto advanceourunderstandingoftheneuralcircuitrymediatingdiscriminationamongemotionallyrelevant environmentalcuesinbothmaleandfemalesubjects,therebyincreasingourknowledgeata systems/circuitslevelofpossiblesexdifferencesinemotionaldisorders.Determininghowneuralcircuit sexdifferencesaregeneratingsexdifferencesinsafety-fear-rewarddiscriminationwillimprovefuture developmentofsex-specificbehavioralanddrugtreatmentsinindividualsdiagnosedwithemotion dysregulationdisorders.